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The NMDA receptor competitive antagonist CPP modulates benzodiazepine tolerance and discontinuation
J M Koff1, G A Pritchard, D J Greenblatt
1Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Mass. 02111, USA.
Pharmacology
|December 17, 1997
Summary
The glutamatergic system plays a role in benzodiazepine tolerance and discontinuation. Co-administering an NMDA antagonist with lorazepam attenuated tolerance and withdrawal symptoms in mice.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Benzodiazepine discontinuation causes withdrawal symptoms similar to glutamatergic system effects.
- The role of the glutamatergic system in benzodiazepine tolerance and withdrawal is not fully understood.
Purpose of the Study:
- To investigate the involvement of the glutamatergic system in benzodiazepine tolerance and discontinuation.
- To examine the effects of NMDA receptor antagonism on lorazepam tolerance and withdrawal.
Main Methods:
- Mice received chronic administration of lorazepam, an NMDA antagonist (CPP), or both via osmotic pumps.
- Evaluated pentylenetetrazole-induced seizure threshold, open-field activity, and benzodiazepine receptor binding.
Main Results:
- Lorazepam alone led to tolerance to its anticonvulsant effects and reduced seizure threshold upon discontinuation.
- Coadministration of CPP with lorazepam attenuated tolerance and abolished the reduction in seizure threshold during withdrawal.
- Benzodiazepine receptor binding decreased during chronic lorazepam administration but increased upon discontinuation, an effect abolished by CPP.
Conclusions:
- The glutamatergic system is involved in the development of benzodiazepine tolerance.
- NMDA receptor antagonism can mitigate benzodiazepine withdrawal symptoms and receptor binding changes.